Sulfonamide derivatives



Patented July 13, 1948 I Zoltan Fiildi, Arpad Gerecs, Istvan lienijn, and Rezsr'i, Kiinig, Budapest, Hungary i vested in the Attorney General of the United-States No Drawing. Original application June 24, 1940,

- 'Serial No; 342,190. Divided and this application April 10, 1941', Serial No. 387,980. In Hungary October 3, 1939 The present invention relates to new Z-aminothiazole derivatives of anticoccic action, as well as :new Z-amino-thiazole derivatives, which are suitablestarting-materials to prepare new .2 amino-thiazole derivatives of anticoccic action. These derivatives are, 2-arylsulphamido-4-oxythiazoles, in which the aryl groupfcontains in the para-position a member of the group consisting of amino-, 'acylamino-,, alkylamino acylated alky1amino-, nitro-groups, as substituent. The term aryl as is obvious from the following disclosure is intended to mean the phenyl radical.

Valuable startingmaterials areftheacylaminoaryl sulpho thioureas, as well as the thioureides oi' heteroc'yclic aminosulphonic acids, such as the acylamino-pyridine-sulphonyl-thiourea. *Arylsulphonyl derivativesof the thiourea have been unknown until now, especially such" arylsul phonyl-thioureas or thioureides of heterocyclic s'ulphonic acids, in which the aryl'group or the heterocyclic nucleus contains amino or substituted' oracylatedamino groups, or other groups which are convertible into the groups enumerated before. The thiourea can not beacylated by acylating agents g'enerally'used for introduction of arylsulphonyl groups, because other reactions take place. Processes indeed must-have been devised,- thus, in orderto obtainthe starting materials for the present invention. These new startingmaterials can be obtainedby splitting oif the a-alkoxy-alkyl group from the S-;(a.-alkoxy-alkyD-ethers oi the iso-thiourea acylated by an aromatic; or heterocyclic sulphonic acid group.

The starting materials for the'latter process were unknown until 'iiow' These starting" materials can be obtained by subjecting iso-thiourea-ethers to the action of acylating agents suitable to introduce arylsulphonic groups or heterocyclic sulphonic acid groups. Such acylating agentsare for example the arylsulpho halogenides, especially those,i1 1 which the arylgroup is substituted by amino, 'alkylamino, acylaminogroups or groups (such as nitro, azo,retc-.';' groups) convertible into'the groups mentioned before.

f6 Claims. (oil zen-239.6)

I iso-thiourea-alkoxy-methyl ethers are preferably and. so forth.

use d in the form of their salts, asthe free bases themselves areunstable. When usingthesalts, itjis preferable to use acid binding agents, such' as pyridine, sodium acetate, sodium alcoholate,

' Further details of theprocess for the obtain ing] of arylsulpho-iso-thiourea-ethers are to be fo'u'ndin'the examples. fTheremoval of the alkoxy alkyl group from thearyl-sulpho-iso-thiourea etherscan be, 'pref-' erably, effected by alcoholysis'. Especially for this splitting off those arylsulpho-iso-thioureaa kyl ethers are suitable'in which'the alk'yl group is an 'alkoxy-methyl or phenoxy-methylgroup; preferably an'ethoxy-methyl or methoxy-methyl group. The alcoholysis is effected, preferably, in the presence of acid catalysts, suchfias" dry'hy drochloric acid. The alcoholysis is efifectedjin an absolute alcohol, containing 0.1-0.3 percent of dry hydrochloric acid. As alcohol, the methylor'ethyl alcohol can be advantageously used. The'alkoxy5methyl groups are split off by this alcoholysis in form ofv acetales offor-maldehyde. Asj starting materials for this hydrolysis'acyl amino' arylsulphoor nitro-aryl-sulpho-iso-thio urea-alkoxy methyl ethers can be preferably used. 7 'Further details of the found'in the examples.

As other components for the process of the present invention arethe a-halogenated acids or its 'ethers or d-haloge'nated derivatives of di-' or poly-carboxylicjacids or of'their esters. Such compounds are for example the chloro-acetic acid, the chlor'oacetic acid ethylester, the bromoor chloro-malonic acid diaethyl ester; the chloro- .cyan-acetic acid-ester, etc. i I

I alcoholysis are to: be

j,, ,The'reaction between the arylsulpho -thiou'rea and the (at-halogenated oxo-compound is preferably carried out in the presence of an'acid bind-- Such acylating agents are for example the such as Pyridine-sulphonyl halogenides can also be used,

for example the 2-acetamino-pyridine-5-sul- One may-use, preferably, as

methoxy-methyl or ethoxy-methyl ethers. These :ir'ig agent, suchas pyridine or other tertiary heterocyclic bases.

" Further details concerning the preparation of "the'starting materials and of the end-products are to be found in the-examples.

(1) Thiourea and chloro-m'eth'ylether are brought into interaction in acetone at room-temperature. The hydrochloride oi the iso-thioureamethoxy methyl-ether separates. It melts at about 102.

' 300 ccs. of absolute methylalcohol are cooled fto 10 and 62.4 grams of chlor'hydrate'of isothiourea-meth'oxy-methylether are added.- While stirringflthe hydro chloride dissolves. Now ascdium-methylate solution is added in portions at 10. The sodium-methylate solution has been prepared from 8.5 grams of sodium and 300 005. of absolute methylalcohol. After the sodiummethylate solution has been added, 42 grams of finely powdered p-acetamino-benzosulpho-chloride are added in portions at -10", while stirring. The stirring is continued at l, then for about one hour at about 0. The p-acetamino-benzolsulpho-iso-thiourea-methoxy methylether separates as a crystal mass. It is now filtered, the precipitate washed with water in order toeliminate the sodium chloride, then dried. One obtains about 40 grams of a White crystalline product, which melts at about 167. It can be recrys tallisated from alcoh'ol.

One may prepare similarly the correspondin products, starting from benzolsulpho-chloride or from p-nitro-benzolsulpho-chloride or from 2- acetamino-pyridine--sulphonyl bromide.

(2) 37.6 grams of finely powdered p-acetylamino-benzol-sulpho-iso-thiourea-methoxy-methyl ether are boiled for a minute in 222 ccs. of 99% methyl-alcohol and 1.1 cos. of absolute ethylalcohol, containing 33% hydrochloric acid gas. The starting material passes into solution and crystallisation occurs soon. The mixture is boiled for further 2 minutes, then allowed to cool,then cooled by ice-water. The crystals are filtered. One obtains 25-28 grams of p acetylamino-benzolsulpho-thiourea, as a white crystalline powder, which melts at about 200.5. It dissolves in diluted alcohol and can be reprecipitated without alteration by acidification with acetic acid.

The splitting ofi of the methoxy-methyl group can be efiected also in ethylalcoholic medium. Instead of the methoxy-methyl-ether of the pacetamino-benzolsulpho-iso-thiourea, one may use the ethoxy-methyl-ether or the a-ethoxyethyleth'er as Well. Instead of the p-acetaminobenzolsulpho-iso-thiourea ethers one may use the corresponding p nitro-benzolsulpho-iso-thiourea ethers; One obtains, in this case, the p-m'trobenzol-sulpho-thiourea. From 2-.acet-aminopyridine-5-sulpho-iso-thiourea-methoxy-methyleth'er one obtains the 2*acetamino-pyridine-5- sulpho-thiourea.

(3') 7.5 grams of ethyl .chloro-acetate, 16.5 grams of p-acetamino-benzolsulpho-thiourea and 18 ccs. of pyridine are mixed. The temperature rises to about 40 and a dissolution occurs. After heating on the waterbath for about a quarter of an hour, the mixture is diluted by 150 ccs. of water, upon which the p-acetylamino-benzolsulpho-2-amino-4--oxy-thiazole separates as a crystalline powder. The yield is about 75% of the theory. It decomposes at 258-259.

(4) 12.5. grams of ethyl chloro-acetate, 23 grams of p-amino-benzolsulpho-thiourea and 30 cos. of pyridine are mixed. A slight elevation of the temperature takes place and the materials go into solution. The mixture is then heated on a water-bath for half an hour, then diluted by 150 cos. of warm water. On cooling the p-aminobenzol-sulpho-2-amino-4-oxy thiazole crystal lises in compact crystals, melting at 235-37". The yield is about 60% of the theory.

(5) 4 grams of chloro-malonic diethyl ester,

5.5 grams of p-acetamino-benzolsulpho-thiourea and 6 ccs. of pyridine are mixed, then heated at about 60 for a quarter of an hour. One obtains a'homogeneous yellow syrup, which solidifies after standing for 2 hours. On addition of 70 cos. of water, the crystals dissolve, followed soon by precipitation of white crystals. One obtains 7.05

grams of crystals, melting at 164 under development of gas. The product is recrystallisable from alcohol, the melting point rising thus to 165-166". The product is the -oxy-derivative of p-acetamino benzol sulpho 2 amino-'S-carbethoxythiazole.

(6) 4.8 grams of bromo-malonic diethylester, 4.6 grams of p-amino-benzol-sulpho-thiourea and 6 cos. of pyridine are mixed upon which the temperature rises to about 75. The yellow thick syrup thus formed, is heated on the waterbath for lo minutes, then allowed to stand for an hour and a half, and then diluted by ccs. of water. The homogeneous solution deposits 5.9 grams of pale yellow crystals, which melt between 136-138.

This product recrystallised from alcohol melts at 138 139", under decomposition. The product is the deacetylated derivative of the product described in the preceding example.

The experimental conditions given in the examples can be varied in many other respects as well.

As well known, 4-oxy-thiazoles show a'tautomerism between the two following formulas:

OH 6:011 OO-0H5 11 & 11 t O O In the present invention a nomenclature according to the left-hand formula. has-been chosen.

This application. is a division of the Foldi, Gerecs, Demjn and Konig application 342,190 filed June-24, 1940. now Patent No. 2,332,906, dated October 26, 1943.

What-we claim is:

1. New compounds ofthe class consistingloi 2-pheny1su1famido-4-oxy-thiazoles and z-phenylsulfamido--oxo-thiazoles, in which the phenyl group contains in the para-position a member of the group consisting of: amino-, acylamino-, alkylamino-, nitro-groups, as substituent.

2. As a new product'the p-acetylamino benzolsulpho-2-amino-4-oxy-thiazole.

3. As a new product the p-amino-benzolsulphoz-aminoi-oxy-thiazole.

4. A compound having a formula of the class consisting of:

and-

in which X is a member or the class consisting of and amino, acylamino, alkylamino, and nitro groups.

H H 0 OH;CON- S0;NC/ ZOL'I'AN F6LDI.

1'1 H H H \N-C a ARPAD GERECS.

5 Is'rvAN DEMJEN.

II 6. Compounds containing a radical of the class REZSO K6NIG. consisting of H H 10 REFERENCES CITED g k l The following references are of record in the H H N-O= file of this patent: and FOREIGN PA'I'E'NTS H H x 15 Number Country Date H H 517,272 Great Britain Jan. 25, 1940 

